Disabled cell density sensing leads to dysregulated cholesterol synthesis in glioblastoma
Diane M Kambach1, Alan S Halim1, A Gesine Cauer1
1Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in astrocytes but not in glioma cells. Here we report that glioma cells have disabled the normal controls on cholesterol synthesis. At high cell density, astrocytes turn off cholesterol synthesis genes and have low cholesterol levels, but glioma cells keep this pathway on and maintain high cholesterol. Correspondingly, cholesterol pathway upregulation is associated with poor prognosis in glioblastoma patients. Densely-plated glioma cells increase oxygen consumption, aerobic glycolysis, and the pentose phosphate pathway to synthesize cholesterol, resulting in a decrease in reactive oxygen species, TCA cycle intermediates, and ATP. This constitutive cholesterol synthesis is controlled by the cell cycle, as it can be turned off by cyclin-dependent kinase inhibitors and it correlates with disabled cell cycle control though loss of p53 and RB. Finally, glioma cells, but not astrocytes, are sensitive to cholesterol synthesis inhibition downstream of the mevalonate pathway, suggesting that specifically targeting cholesterol synthesis might be an effective treatment for glioblastoma.
Insights
Glioblastoma cells evade growth inhibition by maintaining high cholesterol synthesis, unlike normal astrocytes. Inhibiting this cholesterol pathway offers a potential therapeutic strategy for glioblastoma treatment.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Cellular transformation involves evading contact-dependent growth inhibition.
- Identifying therapeutic targets for glioblastoma (GBM) is crucial.
- Investigating pathways differentially regulated by cell density in astrocytes versus glioma cells.
Purpose of the Study:
- To identify pathways dysregulated in glioblastoma cells compared to normal astrocytes.
- To explore the role of cholesterol synthesis in glioblastoma.
- To evaluate cholesterol synthesis inhibition as a potential GBM therapeutic strategy.
Main Methods:
- Comparative analysis of gene expression and metabolite levels in high-density astrocytes and glioma cells.
- Assessment of metabolic pathways including cholesterol synthesis, oxygen consumption, aerobic glycolysis, and pentose phosphate pathway.
- Correlation analysis between cholesterol pathway markers and patient prognosis.
- Evaluation of sensitivity to cholesterol synthesis inhibitors in glioma cells.
Main Results:
- Glioma cells exhibit dysregulated cholesterol synthesis, maintaining high levels and pathway activity even at high cell density, unlike astrocytes.
- Upregulation of the cholesterol pathway in glioblastoma correlates with poor patient prognosis.
- Densely-plated glioma cells utilize increased oxygen consumption, aerobic glycolysis, and pentose phosphate pathway for cholesterol synthesis, leading to reduced ROS, TCA intermediates, and ATP.
- Constitutive cholesterol synthesis is linked to cell cycle control, p53, and RB status.
- Glioma cells are sensitive to inhibition of cholesterol synthesis downstream of the mevalonate pathway.
Conclusions:
- Glioma cells disable normal controls on cholesterol synthesis, contributing to their aggressive phenotype.
- Targeting cholesterol synthesis represents a promising therapeutic avenue for glioblastoma.
